The failure of T cell tolerance can lead to spontaneous inflammation and at worst autoimmune disease. The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells. 4-1BB (CD137, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, was originally identified as an inducible co-stimulatory molecule on activated T cells. The ligand of 4-1BB (4-1BBL, TNFSF9), a member of the TNF super-family, expressed on activated APC binds to 4-1BB that is induced on T cells, generating positive signals inside T cells to help them function and to augment various aspects of immunity. In contrast we have found an inhibitory role for 4-1BB that does not rely on interaction with 4-1BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1BBL-deficient mice. Our hypothesis is that 4-1BB binds with unidentified ligands that are constitutively expressed or induced early in an immune response to limit T cell reactivity and maintain tolerance, but by switching partners to 4-1BBL expressed later with inflammation, 4-1BB can then provide a positive stimulatory action. Our preliminary results have identified both galectin-3 and galectin-9, two reported suppressive molecules, as partners for 4- 1BB. The studies in this grant will investigate the interaction of galectins with 4-1BB and determine whether 4-1BB/galectin interactions account for 4-1BB negatively regulating T cell responsiveness. The identification and characterization of novel binding partners for 4-1BB will provide new understanding into 4-1BB biology as well as T cell tolerance and chronic inflammation. PUBLIC HEALTH RELEVANCE: 4-1BB and its ligand(s) are expressed on the surface of many immune cells and are thought to regulate the ability to mount an immune response. 4-1BB provides essential signals to a T cell to allow it to continue dividing late in its response, and to suppress excessive death. However, 4-1BB interactions also act as a rate-limiting step to control initial T cell division and expansion. By understanding where and when 4-1BB and its ligand(s) are expressed, and the functional importance of these putative interactions, we will gain knowledge that might lead to ways to either enhance or suppress T cell responses, and so might be therapeutically relevant in a number of disease settings such as in limiting autoimmunity, or augmenting the ability to respond to cancerous cells or infectious pathogens.